Normal turnover of the extracellular matrix is a well-regulated process: molecules that are degraded, mostly by proteinases, are lost from the tissue and replaced by newly synthesized ones. Changes in the metabolism of articular chondrocytes within a synovial joint, such as occur during aging or following trauma to a joint, give rise to progressive changes in the physicochemical properties of this extracellular matrix, predisposing some of the joints (e.g. the knee joint) to osteoarthritis (OA). It is widely accepted that "OA is an attempted but failing repair": anabolic processes (repair response) that predominate during the early stages of the disease, fail over the long term to keep up with the enhanced catabolic response of the articular chondrocytes. The extent to which changes in gene expression contribute to the progressive destruction of the articular surface is not clear. At this time, it also is not known if those osteoarthritis associated changes in expression of matrix-related genes are reversible or not. In other words, it is not clear if those chondrocytes can, at all stages of the disease, regain the normal chondrocytic phenotype when they are moved into a suitable environment. During the previous funding period, we made the exciting discovery that normal human adult articular chondrocytes allowed to rapidly reform a small cell-associate matrix in alginate gel will, when subsequently cultured upon a semi permeable membrane, reform a functional cartilage tissue in vitro. This original scaffold-free culture system, termed the "Alginate Recovered Chondrocytes" (ARC) method, will be used to identify morphological and biochemical similarities and differences in the abilities of normal and CIA articular chondrocytes to reform a cartilaginous tissue in vitro. Studies will be performed with the goal of identifying mechanisms playing key roles in cartilage matrix formation and maturation Experiments will then be performed to determine the feasibility of manipulating the expression of specific genes to alter the metabolism of CIA chondrocytes and to overcome specific deficiencies in the ability of these OA cells to produce a normal matrix.